The long-term objective of this proposal is to understand the cellular and molecular mechanisms that underlie the development of chronic inflammatory pain. Specifically, this proposal is designed to assess the role that peripheral metabotropic glutamate receptor 5 (mGluR5) plays in inflammation-induced pain and hypersensitization. Evidence from pharmacological studies indicates that mGluR5 plays a critical role in the development and maintenance of chronic pain. However, the molecular mechanisms through which mGluR5 activation induces hypersensitivity are unclear. In addition, mGluR5 is expressed throughout the nervous system, but the specific role of mGluR5 expressed in peripheral nociceptive sensory neurons (nociceptors) is unknown. I will address both of these issues through the experiments in this proposal. First, I will test the hypothesis that peripheral mGluR5 is required for the full expression of inflammatory pain. To test this hypothesis I will asses the pain related behaviors of a line of genetically modified knockout mice that lack mGluR5 only in peripheral nociceptors. Second, I will address the molecular mechanisms underlying mGluR5-induced hypersensitivity. These changes have been suggested to be due to the modulation of cation channels expressed on peripheral nociceptors. Both mGluR5 and the inflammatory mediator bradykinin activate PLC-coupled intracellular signaling cascades. Interestingly bradykinin activation results in the activation of the nociceptive cation channel Transient Receptor Potential A1 (TRPA1). The common PLC-coupled intracellular signaling cascade shared between bradykinin receptor and mGluR5 suggests that mGluR5 may modulate TRPA1. In this proposal I will test the hypothesis that mGluR5 activation can modulate TRPA1 in nociceptors. I will utilize in situ hybridization and calcium imaging to assess for mGluR5 and TRPA1 colocalization in nociceptors. Then I will assess whether mGluR5 activation can modulate TRPA1 mediated responses in dorsal root ganglia neurons in vitro. Finally I will determine whether pharmacological mGluR5 activation differentially affects the in vivo pain behaviors of TRPA1 KO mice as compared to their wildtype littermates. PUBLIC HEALTH RELEVANCE: The experiments in this proposal will provide critical insight into the role of peripheral mGluR5 in chronic pain and the molecular mechanisms through which mGluR5 activation results in hypersensitivity. An improved understanding of both the role of peripheral mGluR5 in inflammatory pain, and the signaling mechanisms underlying mGluR5-induced hypersensitivity, will directly guide both future pain research and the development of therapeutic interventions for the treatment of human inflammatory pain conditions.